Objective The primary objective is to explore the clinical and biological phenotypes of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). The secondary objective is to explore the pathophysiology of fatigue and post-exertional malaise (PEM). Study population Up to 186 persons will be enrolled as part of this protocol. Up to 150 persons aged 18-60 will be part of 3 study groups: 50 ME/CFS patients whose fatigue began after an infection, 50 non-fatigued participants with a documented history of Lyme disease exposure and treatment, and 50 healthy volunteers. The study has a target of completing all study procedures on 20 enrolled participants in each group. Up to an additional 36 persons reporting a community diagnosis of ME/CFS will be enrolled into focus groups to discuss the experience of post-exertional malaise. Design This is a single-center, exploratory, cross-sectional study of PI-ME/CFS. Participants will have a phenotyping visit, which will encompass a 2-5 day long inpatient admission at the NIH Clinical Center. Case status for ME/CFS participants will be determined after the phenotyping visit by a case adjudication process utilizing an expert physician committee and published guidelines. Adjudicated participants meeting inclusion criteria will be invited back to participate in an exercise stress visit, which will encompass a 5-10 day long inpatient admission. Detailed subjective and objective measurements and biological specimens will be serially collected before and up to 96 hours after a peak exercise test capable of inducing post-exertional malaise during this visit. All procedures will be completed on all three study groups to allow for optimal inter-group comparisons. Outcome measures 1. Characterization of the immune system and inflammatory signaling in blood and cerebrospinal fluid (CSF) 2. Characterization of the pattern of microbiome in gut, blood and CSF 3. Characterization of physical and cognitive fatigue using functional magnetic resonance imaging and transcranial magnetic stimulation 4. Effect of maximal exertion on neurocognition 5. Effect of maximal exertion on brain function and connectivity 6. Effect of maximal exertion on markers of immune dysfunction and inflammation 7. Effect of maximal exertion on metabolic function 8. Effect of maximal exertion on autonomic function 9. Effect of maximal exertion on gene expression profiles in blood and CSF